4-amino-6-trifluoromethyl-n, n&#39;-di-2-pyridyl-m-benzenedisulfonamide



j 4 AMINOb-TRIFLUOROIVIETHYIAMN-DI-Z-PliRI- DYL-m-BENZENED I SULFONAMDJELee C. Cheney, Fayetteville yand Charles T. Holdrege,

I 'Camillus, N.Y., assignorsy by mesne assignments, to

Bristol-MyersyCompany, New York, N.Y., a corporation of'Delaware NoDrawing, Filed June is, 1959, Ser. No. 820,125

4 'Claims. 01. 260239.65)

This invention relates to novel diuretic and natriuretic compounds oftherapeutic value and, more particularly, to 4 amino 6 trifluoromethylN,N di 2 pyridy1 n-benzene-disulfonamide and nontoxic metal salts there-In the treatment of many diseases characterized by an excessiveaccumulation of water in the body, such as the edem'as associated withcongestive heartfailuretoxemia of. pregnancy, tension, and in thealleviation of salt retention caused by therapy with certain steroidssuch as cortisone, the physician requires an agent which will cause thebody to excrete water. vPrevious agents used for-this purpose have hadmany drawbacks. Thus, ammonium salts are not very effective and causeacidosis, xranthine derivatives do not remove water already stored inthe body, carbonicanhydrase inhibitors are not very eflfective and causeundesirable side effects and'organic mercurial compounds retain theireffectiveness only for limited periods of time, are toxic by nature andmust normally be given by injection; 1 It isthe object. of thepresentinvention to-provideIa therapeutic agent oi the diuretic typewhich is highly potent even on prolonged use and does not cause toxic drefle :Q ndesirable meta o q d stu h nc ss as excessive potassiumexcretion and, preferably, acts by causing the body to excrete roughlyequal amounts of sodium and chloride ions.

The object of the present invention has been attained by the provision,according to the present invention, or-

a member selected by the group consisting of a compound having theformula F30 NH, L HNOzS SOINH \N and nontoxic metal salts thereof.

The compounds of the present invention are converted to nontoxic metalsalts including calcium, magnesium and aluminum salts and preferably toan alkali metal salt such as sodium or potassium, by treatment with oneequivalent of alkali, e.g. one equivalent of aqueous sodium hydroxide.The compounds of the present invention are administered orally in theform of capsules or tablets or, if desired, parenterally as aqueoussuspensions or as solutions in dilute aqueous alkali or in nontoxicorganic solvents of the hydroxylic type. Dosage is, of course, at thediscretion of the physician but representative daily dosages, which maybe given in one dose or be divided and given at intervals, tall in therange of 200 mgm. to 3 g. and preferably 500 to 1000 The product of thepresent invention is prepared by the reaction of 4 amino 6nifluoromethyl-L3-benzenedisulfonyl chloride with at least two moles of2-aminopyridine, preferably in a solvent such as tetrachloroethane. Usemay be made of a tertiary base such as pyridine or of an excess ofZ-aminopyridine as an acceptor for the hydrogen chloride generated. Thereactionis carriedoutbetween room temperature and about 100 C. andproceeds more rapidly at higher temperatures.' f 1A, solutionof thestarting reagent, 4-amino-6-trifl-uoromethyl-1,3Pbenzene ,dis'ulfonylchloride, in tetr'achloroethane'is conveniently obtained by thefollowing proceidurez'; I 1T0 'af-reactionvessel chilled in an icebaththere is ad-ded 750.ml'. (11.5 mole) chlorosulfonic acid and 1500.Itetra'chlor'oethane. m-Aminobenzotrifluoride (130 'm 1 ';16-1 g.,1:.0mole) is then added slowly with stirring overa'fifteen'-rninute'pe1iod. The ice bath is removed and/100g. (12 'Inole)sodium chloride is added slowly with "stirring overja period of -30minutes. The reaction mixture. is then stirred and heated slowly to 120C. (e-g. over one hour), held at 120 C. for about thirty minutes (anddesired held an additional thirty minmean 120 C.') "and then' cooled asrapidly as possible to 30 C. or less. The reaction mixture is quenchedby pouring rapidly on a stirred mixture of 4.5 1. ice cubes, plus 3 1.cold water with the temperature of the quench i mixture kept below 20 C.The mixture is then stirred for fifteen minutes and filtered. Thefiltrate (A) is separatedlandzthe solvent layer (S-1) and water layer(W-l) Jaresavedh The tarry cake is slurried in 500 ml, tetrachloroethaneto remove adhering rich solvent and 1 product. This mixture is thenfiltered and the solvent phase "(S2) is stirred with previous waterphase (W-l). The solvent layer is separated and added to solvent phase(8-1). The combined solvent phases constitute the desired solution intetrachloroethane of 4-'amino-6-tri-.

; fluoromethyl-l,3rbenzenedisulfonyl cyhloride.

- Upon intravenous administration in solution at 2% in dilute aqueoushydroxide in dogs at a dosage 'l'OJ mgm kgl, the4-amino-6-trifluoromethyl-N,N'-di+ 2pyridyl-m-benzenedisulfonamideproduced an increase of about 200-fold in urinary output of sodium ionas compared to contro'ldogs injected 'with saline and an increase ofseven to ten-fold over that produced by injection of the same dose ofthe known, highly potent natriuretic agent 6 trifiuoromethyl 7sultamyl-3,4-dihydro-1,2,4-ibenzothiadiazine-1, l adioxide.

One 'of the most surprising features of the present invention is thefinding of potent natriuretic activity for the compound of the presentinvention in view of the absence of such activity in the closely relatedcompounds having the =following formulae:

F: C NHi RHNOzS- S OzNHR where R is methyl (M.P. 168-170 C.) or ethyl(M.P. 177181 C.).

The following examples are given to illustrate the scope of thisinvention without limiting it thereto.

' Example 1 One liter of tetrachloroethane containing 40 g. (0.112

mole) 4-amino6 -trifluoromethyl-l,3-benzene disulfonyl of concentratedNH OH. The oil was readily soluble.

The aqueous ammoniacal solution was separated and heated four hours onthe steam bath to expel ammonia. After chilling in an icehath a viscousoil separated. The aqueous phase was decanted and discarded.

A layer of dark-.

Water (500 ml.) was added to the residue and the mixture Was heated toboiling with stirring. The hot aqueous solution was decanted frominsoluble material and discarded.

The insoluble material was air-dried and found to weigh 15.6 g, to beinsoluble in Water, methanol and acetone and to be soluble in pyridineand sodium hy- 'droxid'e. pyridine, which was filtered to removeinsoluble material which weighed 4.8 g. after drying in air and meltedat 288-291 C. on .an aluminumhlock. This material was dissolved at about100 C. in a minimal amount of dimethylformamide and the solution wasfiltered,'diluted with water, cooled and scratched to precipitatecrystalline product, 4 amino 6 triiluoromethyl- N,N-di 2-pyridyl-rn-benzene-disulfonamide, which was collected, found to melt at293-295 C. (d.) and again recrystallized in the same manner, found tomelt at 293-294 C. dec. (Al block) and dried in vacuo at 65 C. over Pand found to weigh 3.34 g.

Analysis.-Calcd for C H F N O S C, 43.2; H, 2.98. Found: C, 43.43; H,3.22.

Example 2 To 2-aminopyridine (282 g., 3 mole) and 1 l. pyridine placedin a 12 l. flask a solution (3.8 l.) of tetrachloro ethane containing302 g. (0.849 mole) of 4-amino-6-trir fluoromethyl-1,3-benzenedisulfonylchloride was added in It was then extracted with 60 ml. boiling portionsover a period of 20 minutes to give a moderate ly exothermic reaction.The maximum temperaturewas C. The mixture was stirred six hours withoutheating or cooling and was then at 30 C. After standing overnight atroom temperature, the mixture was heated at -78 C. for seven hours,cooled to room temperature and washed with stirring with 4 1. and then3 1. water. The aqueous phase was removed by siphoning. A quantity ofgummy dark brown solid floating on top of the tetrachloroethane wasseparated by siphoning ofi the tetrachloroethane, stirred 15 minutes. inone liter methanol, collected by filtration, washed on the filter with 5portions of methanol and found to melt at about 260265 C. and to weigh163 g. This product was dissolved by heating to boiling in 700 ml.dimethylformamide. The solution was filtered hot to remove someinsoluble material, designated solids A. The filtrate was diluted with400 ml. water, scratched and cooled to precipitate g. crystalline4-amino-6-t1ifluoromethyl-N,N'- di-2-pyridyl-rn-benzenedisulfonamide,M.P. 289293 C. This product was. recrystallized by dissolving in 500 ml.boiling dimethylformamide, treating with carbon, filtering, adding theml. dimethylformamide used to wash the carbon on the filter and dilutingwith 35.0 ml. water to precipitate crystalline product which wascollected, washed wtih methanol, dried and found to weigh 61 g. and tomelt at 290292 C. (dec.). This lot weighed 60.8 g. after drying in vacuoover P 0 An additional amount of product was obtained from the abovementioned solids A by dissolving it in 500 ml. boilingdimethylforrnamide, filtering, diluting with 300 ml. water, cooling andscratching to precipitate crystalline product which was collected byfiltration, washed with methanol, sucked dry and foundto Weigh 34.6 g.and to melt at 293294 C. (dec.). This lot weighed 29.3 g. after dryingin vacuo over P 0 The melting points given above were taken in acapillary in an aluminum block.

We claim:

1. A compound selected from the group consisting of 4 amino 6trifiuoromethyl N,N' di 2 pyridyl-mbenzenedisul'fonamide and nontoxicmetal salts. thereof.

2. 4 amino 6 trifiuoromethyl N,N di 2 pyridyl-rn-benzenedisnlfonamide.

3. An alkali metal salt of 4-amino-6-trifluoromethyl- N',Ndi-2-pyridyl-m-benzenedisulfonamide.

4. Asodium salt of 4-amino-6-trifluoromethy1-N,N-

di-2-pyridyl-rmbenzenedisulfonamide.

OTHER REFERENCES Kulka: Can. J. Chem., vol. 32, pp. 598-605 (1954). 5

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF4-AMINO-6-TRIFLUOROMETHYL-N,N''-DI-2-PYRIDYL-MBENZENEDISULFONAMIDE ANDNONTOXIC METAL SALTS THEREOF.